Bone undergoes a continual remodeling process that requires the coordinated activity of two types of cells. Osteoclasts break down the bone matrix while osteoblasts deposit collagen, calcium, and phosphorous and other minerals to form new bone. The balance between the activity of osteoclasts and osteoblasts determines the mass and density of the bone. Many diseases of bone including osteoporosis, a common age-related phenomenon in post-menopausal women in which the bone mass has been greatly reduced, and osteogenesis imperfecta, also known as brittle-bone disease, are likely caused by the misregulation of osteoblasts and osteoclasts.
According to National Osteoporosis Foundation, osteoporosis alone currently affects about 44 million Americans. In addition, almost 34 million Americans are estimated to have low bone mass, placing them at increased risk for osteoporosis. By 2025, the annual direct costs of treating osteoporosis fractures in the US are estimated at $25 billion per year. Therefore, understanding the molecular mechanisms that underlie osteogenesis, the process by which new bone is formed, is of critical importance to improving the tools and methods for treating bone related diseases.
In this respect, stem cell technology, particularly mesenchymal stem cells (MSCs), offers an attractive sources of osteoblasts for tissue culture studies and for the biochemical dissection of the earliest steps involved in osteoblast cell determination. MSCs have the capacity for self-renewal and for differentiating into a variety of cells and tissues. Because of their multipotency, ease of isolation and culture, and immunosuppressive properties, these cells are also an attractive therapeutic tool for regenerative medicine. Given that autologous cells may be used for the eventual therapies, MSCs are particularly attractive in the context of bone and cartilage repair as well as other reconstructive applications. Clinical trials of MSC-based therapies are already underway for a number of diseases, including osteogenesis imperfecta, mucopolysaccharidoses, graft-versus-host disease, and myocardial infarction.
However, progress in MSC-based cell therapy for skeletal defects has been hindered by the MSCs' limited cell life-span and the fact that they progressively lose their osteogenic potential during ex vivo expansion. Further, the complexity of the signaling pathways that promote MSCs towards osteogenic differentiation poses significant challenges for in vivo application of MSCs. For example, the canonical Wnt-beta cantenin, bone morphogenetic protein (BMP), and extracellular matrix (ECM)-mediated Ras-Erk signally pathways have all been implicated in playing a critical role in the differentiation of MSCs to osteoblasts and in bone formation, but there is still no consensus as to how they work together in vivo. Thus, precise manipulation of MSCs in terms of inducing and stopping their osteogenic potential has been difficult.
To induce osteogenicity in MSCs, a number of ECM factors such as collagen type I and vitronectin, have been found to be effective. It has been reported that the greatest osteogenic differentiation occurred in MSCs plated on vitronectin and collagen type I and almost no differentiation took place on fibronectin or uncoated plates. Although it has been accepted that proteins and growth factors present in the ECM can drive stem cell differentiation by regulating gene expression, the sheer number of factors that exist in the ECM and the vast variety of signaling pathways interacting with each other render it virtually impossible to predict a priori the effects of any particular ECM factors. Studies have shown that ECM elements normally found in bone—such as laminin-1, fibronectin, and collagen 1—may have a defining effect on the differentiation of bone marrow progenitors. However, knowledge of the effects of these ECM elements is far from complete.
To advance the field of MSC-based therapy for bone or cartilage damages, more research tools and therapeutic agents capable of inducing and maintaining osteogenicity of MSCs are needed.